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CARCINOGENESIS
THE MOLECULAR BASIS OF CANCER
Mutation in the
Genome of Somatic Cells
Clonal expansion
Additional Mutation
Heterogenecity
Malignant Neoplasm
6 Fundamental Changes
in Cell Physiology
• Self sufficiency in Growth Signals
• Insensitivity in Growth Inhibitory Signals
• Evasion of Apoptosis
• Limitless Replicative Potential
• Sustained Angiogenesis
• Ability to Invade/Metastasize
Self sufficiency in Growth Signals
• Growth Factors
PDGF, TGF-å
• Growth Factor Receptors
ERBB1 (EGF), ERBB2
• Signal Transducing Proteins
RAS, ABL
• Nuclear Transcription Factor
MYC,MYB,JUN,FOS,REL
• Cyclin & Cyclin Dependent
Kinase
Signal Transducing Proteins
GF GF + reseptor
PROLIFERATION
Cyclin & Cyclin Dependent Kinase
CDKI_r21 G0 CDKI_p15
CDKI_p16
CDKI_r27
CDKI_r52 CDKI_p18
CDKI_p19
M G1
CYCLIN
CYCLIN
a_RB CDK 2
CDK 1 CDK 4
i_RB CDK 6
G2 S
CYCLIN
GROWTH
FACTOR
CDK 1
CDK 2
6 Fundamental Changes
in Cell Physiology
• Self sufficiency in Growth Signals
• Insensitivity in Growth
Inhibitory Signals
• Evasion of Apoptosis
• Limitless Replicative Potential
• Sustained Angiogenesis
• Ability to Invade/Metastasize
Insensitivity in Growth Inhibitory
Signals
• RB gene & Cell Cycle
• Transforming Growth Factor β
Pathway
• Adenomatous Polyposis Coli β
Catenin Pathway
• TP 53 gene
RB gene & Cell Cycle
CDKI_r21 G0 CDKI_p15
CDKI_p16
CDKI_r27
CDKI_r52 CDKI_p18
CDKI_p19
M G1
CYCLIN
CYCLIN
a_RB CDK 2
CDK 1 CDK 4
i_RB CDK 6
G2 S
CYCLIN
GROWTH
FACTOR
CDK 1
CDK 2
RB gene & Cell Cycle
G1 S
a_RB i_RB
CYCLIN CDK 2
CDK 4
CDK 6
Adenomatous Polyposis Coli
β Catenin Pathway
WNT reseptors WNT
E-cadherin
signals
APC
APC
β catenin
β catenin APC β catenin
Transcriptional UpRegulation
G No Cell No DNA
Of Target Genes
Cycle Arrest Repair
• Evasion of Apoptosis
• Limitless Replicative Potential
• Sustained Angiogenesis
• Ability to Invade/Metastasize
Limitless Replicative Potential
• Most Normal Human Cells,
have 60-70 doublings
• Telomeres Shortening
• Active RB & TP53
• Active CDKN2A
RB gene & Cell Cycle
CDKI_r21 G0 CDKI_p15
CDKI_p16
CDKI_r27
CDKI_r52 CDKI_p18
CDKI_p19
M G1
CYCLIN
CYCLIN
a_RB CDK 2
CDK 1 TP53 check point
CDK 4
i_RB CDK 6
G2 S
CYCLIN
GROWTH
FACTOR
CDK 1
CDK 2
Normal Cell TP 53 gene AbNormal Cell
[TP 53 normal] [TP 53 AbNormal
Transcriptional UpRegulation
No Cell No DNA
Of Target Genes
Cycle Arrest Repair
Malignant Cells
TP53
Plasminogen Angiostatin
Thrombospondin-1 Collagen Vasculostatin
Transthyretin Endostatin
Other Cells
Platelet F 4
Interferon Alpha
IL-12
Troponin
Maspin
Antiangiogenic Factors
Ability to Invade/Metastasize
• Invasion of Extra Cellular Matrix
• Detachment of tumor cells from each
other
• Attachment of tumor cells to matrix
component
• Degradation of ECM
• Migration of Tumor Cells
• Vascular Dissemination & Homing
of Tumor Cells
Normal Malignant
WNT reseptors WNT
E-cadherin
signals
APC
β catenin
β catenin APC
ECM
fibronectin
integrin
laminin
• Individuals born w/ such a inheritage mutations
of DNA repair Protein are the greatly increase
risk of developing Cancer
• Each cancer, must result from accumulation of
multiple mutations.
• Despite the fact that most malignant tumor are
monoclonal in origin, by the tumor they clinically
evident, their constituent cells are extremely
heterogenous
Tumor Markers Cancer Non-Neoplastic Conditions
HORMONES
Human chorionic gonadotropin Gestational trophoblastic disease, Pregnancy
gonadal germ cell tumor
Calcitonin Medullary cancer of the thyroid
Catecholamines Pheochromocytoma
ONCOFETAL ANTIGENS
Alphafetoprotein Hepatocellular carcinoma, Cirrhosis, hepatitis
gonadal germ cell tumor
Carcinoembryonic antigen Adenocarcinomas of the colon, Pancreatitis, hepatitis,
pancreas, lung, breast, ovary inflammatory bowel disease,
smoking
ENZYMES
Prostatic acid phosphatase Prostate cancer Prostatitis, prostatic hypertrophy
Neuron-specific enolase Small cell cancer of the lung,
neuroblastoma
Lactate dehydrogenase Lymphoma, Ewing's sarcoma Hepatitis, hemolytic anemia,
TUMOR-ASSOCIATED PROTEINS
Prostate-specific antigen Prostate cancer Prostatitis, prostatic hypertrophy
Monoclonal immunoglobulin Myeloma Infection, MGUSa
CA-125 Ovarian cancer, some lymphomas Menstruation, peritonitis,
pregnancy
CA 19-9 Colon, pancreatic, breast cancer Pancreatitis, ulcerative colitis
CD30 Hodgkin's disease, æ
anaplastic large cell lymphoma
CD25 Hairy cell leukemia, æ
adult T cell leukemia/lymphoma
Carcinogens and Associated Cancers or Neoplasms
Carcinogensa Associated Cancer or Neoplasm
Alkylating agents Acute myelocytic leukemia, bladder cancer
Androgens Prostate cancer
Aromatic amines (dyes) Bladder cancer
Arsenic Cancer of the lung, skin
Asbestos Cancer of the lung, pleura, peritoneum
Benzene Acute myelocytic leukemia
Chromium Lung cancer
Diethylstilbestrol (prenatal) Vaginal cancer (clear cell)
Epstein-Barr virus Burkitt's lymphoma, nasal T cell lymphoma
Estrogens Cancer of the endometrium, liver
Ethyl alcohol Cancer of the liver, esophagus, head and neck
Helicobacter pylori Gastric cancer
Hepatitis B or C virus Liver cancer
Human immunodeficiency virus Non-Hodgkin's lymphoma, Kaposi's sarcoma,
squamous cell carcinomas (especially of the urogenital
tract)
Human papilloma virus
Human T cell lymphotropic virus Adult T cell leukemia/lymphoma
type I (HTLV-I)
Carcinogens and Associated Cancers or Neoplasms
Carcinogensa Associated Cancer or Neoplasm
Immunosuppressive agents Non-Hodgkin's lymphoma
(azathioprine, cyclosporine,
glucocorticoids)
Nitrogen mustard gas Cancer of the lung, head and neck, nasal sinuses